Overall Component for the University of Pennsylvania Perelman School of Medicine Morris K. Udall Parkinson's Disease Research Center of Excellence: ?Parkinson's Disease and Dementia? Udall Center Director: J.Q. Trojanowski Udall Center Summary/Abstract: The goals of the competing renewal application for the University of Pennsylvania (Penn) Perelman School of Medicine Udall Center are to elucidate mechanisms of progressive neurodegeneration in Parkinson's disease (PD), especially those that underlie cognitive impairments in PD without and with dementia (PDD) and in dementia with Lewy bodies (LBs) or DLB (Projects I/II) that we refer to collectively as LB disorders or LBD. Udall Center investigators hypothesize that LBD leads to neuron dysfunction and death resulting from the differential transmission of pathologic alpha-synuclein (a-syn) strains leading to the formation of Lewy bodies (LBs) and neurites (LNs) and their neurotoxic effects. Understanding LBD progression and its heterogeneity from molecular to patient levels will advance our ability to develop a precision medicine approach to LBD care and management. Thus, Projects III/IV seek to elucidate the conformationally distinct strains underlying PD, PDD and DLB compared to those underlying multiple system atrophy (MSA) characterized by glial cytoplasmic inclusions (GCIs) formed by misfolded a-syn, while Project I seeks to better clinically manage the diversity of phenotypes within LBD that may result from these strain differences, and Project II extends our analysis of phenotypic diversity to the important area of cognitive decline. Consistent with the mission of the Udall Centers described in the most recent RFA, the vision statement of the Penn Udall Center for the renewal period is to elucidate the progression of PD from normal cognition to cognitive impairment, executive dysfunction and dementia in PDD, as well as disease progression in DLB in addition to neurodegeneration mediated by progressive accumulations of pathological a-syn. The landmark discovery of mutations pathogenic for PD in the a-syn gene, the discovery of pathological a-syn as the disease protein that forms LBs/LNs in PD/PDD/DLB as well as GCI in MSA in addition to evidence for the cell-to-cell spread of a-syn strains places a-syn at center stage for understanding mechanisms of LBD/MSA. The Penn Udall Center renewal seeks to address these key issues in four Projects supported by four Cores including: Administrative Core A: Core Leader (CL) - John Q. Trojanowski; Clinical Core B: CL - Daniel Weintraub, Co-Investigators (Co-Is) - Lama Chahine, Nabila Dahodwala, James Morley, Alice Chen-Plotkin; Neuropathology & Genetics Core C: CL - John Q. Trojanowski; Co-Core Leaders - Edward B. Lee, Vivianna Van Deerlin; Data Management, Biostatistics & Bioinformatics Core D: CL - Sharon Xie, Co-I - Li-San Wang. These Cores support the following Projects to achieve the goals of the Udall Center renewal: Project I ?A Framework for Precision Medicine in Parkinson's Disease?: Project Leader (PL) - Alice Chen Plotkin; Co-I - Dan Weintraub; Project II ?Executive Difficulty in Parkinson's Dementia?: PL - Murray Grossman; Co-Is: Rizwan Akhtar, David Irwin, Corey McMillan; Project III ?Mechanisms of Pathological A-syn Transmission?: PL - Virginia M.-Y. Lee; Project IV ?Pathologic A-syn Strains & Diverse Synucleinopathies?: PL - John Q. Trojanowski; Co-Is - Virginia M.-Y. Lee, Kelvin Luk.